The long term objective of this project is to determine the properties of saliva that endow the oral cavity with unique resistance and immunologic responsiveness to HIV. Previous studies have demonstrated that defensins, host defense peptides involved in innate immunity, are capable of directly inhibiting HIV infection of susceptible target cells. In addition, defensins are known to activate elements of innate and adaptive immunity (T-cells, monocytes, macrophages, dendritic cells), thus providing signals essential for the acquisition of humoral and/or cell-mediated immunity against a variety of microbial pathogens. Defensins are produced in saliva of humans and non-human primates. This project seeks to characterize the role of salivary defensins in regulating immune responses in the oral cavity of rhesus macaques, a primate with a clinical response to SIV infection that is quite similar to that observed in human HIV infection. Recent studies in the PI's laboratory have demonstrated that, in addition to direct anti-HIV activity of defensin subclasses, these peptides also have profound immunomodulatory activities. We hypothesize that immunoregulation by salivary defensins establishes a unique immunologic milieu in oral mucosa that determines the early response of the host to HIV exposure. An understanding of the interactions between defensins and cellular elements of the oral mucosa will provide insights into the network of interactions that determine the immune responses to SIV in the oral cavity. To achieve these objectives, we propose the following Specific Aims: 1) Quantify the a, , and ?-defensin content in whole saliva of healthy and chronically SIV-infected macaques; 2) determine the anti-SIV activity of physiologic concentrations of individual and combined peptides in the presence or absence of defensindepleted whole saliva; 3) determine the effect of individual and combined salivary defensins on the activation profile of PBMCs, monocytes, monocyte-derived macrophages, monocyte-derived dendritic cells, and CD4+ lymphocytes; and 4) Evaluate the effect of salivary defensins on the infectivity of HIV of oral epithelial cells, the response of oral epithelium to bacterial antigens, and the transport of HIV from the epithelial cells to permissive CD4+ target cells. Taken together, these studies will provide new insights into the unique features of immunity in the oral cavity of rhesus monkeys, thereby guiding preclinical approaches to SIV and HIV vaccine development.